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Cancer associated talin point mutations disorganise cell adhesion and migration

Azizi, Latifeh, Cowell, Alana R, Mykuliak, Vasyl V, Goult, Benjamin T, Turkki, Paula, Hytönen, Vesa P (2020) Cancer associated talin point mutations disorganise cell adhesion and migration. BioRxiv, . (Submitted) (doi:10.1101/2020.03.25.008193) (KAR id:80675)

Abstract

Talin-1 is a key component of the multiprotein adhesion complexes which mediate cell migration, adhesion and integrin signalling and has been linked to cancer in several studies. In this study we analysed mutations in talin-1 reported in the Catalogue of Somatic Mutations in Cancer. A total of 11 talin mutants were selected and expressed in talin-deficient fibroblasts and their functional and structural effects were characterised in detail. An I392N point mutation in the F3 domain caused a three-fold increase in invasion, and enhanced migration compared to wildtype talin. Mutations R1368W and L1539P in the R7 and R8 domains caused increased invasion and proliferation and affected talin-vinculin complexation, but were not linked to changes in their binding affinities with known substrates KANK1 and RIAM measured for isolated talin domains. Lastly, L2509P, a mutation in the dimerisation domain of talin, prevented talin dimer formation, actin recruitment and FAKpTyr397 activation leading to anisotropic cell spreading and loss of random migration. Altogether, this study suggests that cancer derived point mutations in talin-1 can drastically affect cell behaviour and so may contribute to cancer progression.

Item Type: Article
DOI/Identification number: 10.1101/2020.03.25.008193
Uncontrolled keywords: talin, COSMIC, somatic mutations, cancer, migration, invasion, focal adhesion
Subjects: Q Science > QH Natural history > QH581.2 Cell Biology
Divisions: Faculties > Sciences > School of Biosciences
Depositing User: Ben Goult
Date Deposited: 31 Mar 2020 13:50 UTC
Last Modified: 02 Apr 2020 16:07 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/80675 (The current URI for this page, for reference purposes)
Goult, Benjamin T: https://orcid.org/0000-0002-3438-2807
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